The rockefeller university

BACKGROUND & AIMS: Hepatic encephalopathy (HE) is a common complication following transjugular intrahepatic portosystemic shunt (TIPS) insertion. However, the prognostic significance of overt HE post-TIPS remains controversial. METHODS: We screened 2137 patients who underwent TIPS insertion at 8 German tertiary care centers between 2004 and 2021. Patients with pre-emptive TIPS placement, hepatocellular carcinoma, missing data, and non-PTFE covered stents were excluded. Competing risk analysis was performed, considering liver transplantation as a competing event. To correct for immortal time bias, landmark analyses were conducted, with the landmark being set at 30 and 90 days post-TIPS. Outcome data were assessed for up to 30 months post-TIPS insertion. RESULTS: A total of 1356 patients (median Model for End-stage Liver Disease [MELD], 13 [interquartile range (IQR), 10-17]; age, 60 years [IQR, 54-67 years]; 64% male; 12% HE before TIPS), were included. Overall, HE post-TIPS was linked to impaired survival (P < .001; subdistribution hazard ratio [sHR], 1.41; 95% confidence interval [CI],1.15-1.73). However, this was only confirmed if HE occurred within the first 30 days post-TIPS (early HE; P < .001; sHR, 2.02; 95% CI, 1.59-2.57). Additionally, patients with a history of HE (P < .001; sHR, 1.59; 95% CI, 1.21-2.07) and history of HE and early HE post-TIPS (P < .001; sHR, 3.44; 95% CI, 2.34-5.04) showed impaired survival. These findings were confirmed in the landmark and multivariable analyses. CONCLUSIONS: Early HE post-TIPS is associated with significantly reduced survival. Therefore, patients who experience early HE or have a history of HE should be closely monitored by physicians, as they constitute a particularly vulnerable group with impaired survival.

Regulatory T (Treg) cells, expressing the transcription factor Foxp3, are obligatory gatekeepers of immune responsiveness, yet the mechanisms by which Foxp3 governs the Treg transcriptional network remain incompletely understood. Using a novel chemogenetic system of inducible Foxp3 protein degradation in vivo, we found that while Foxp3 was indispensable for the establishment of transcriptional and functional programs of newly generated Treg cells, Foxp3 loss in mature Treg cells resulted in minimal functional and transcriptional changes under steady state. This resilience of the Foxp3-dependent program in mature Treg cells was acquired over an unexpectedly long timescale; however, in settings of severe inflammation, Foxp3 loss led to a pronounced perturbation of Treg cell transcriptome and fitness. Furthermore, tumoral Treg cells were uniquely sensitive to Foxp3 degradation, which led to impairment in their suppressive function and tumor shrinkage in the absence of pronounced adverse effects. These studies demonstrate a context-dependent differential requirement for Foxp3 for Treg transcriptional and functional programs.

Over the past decade, radio frequency (RF) sensing or radar has garnered great interest as an emerging modality to enable human-computer interaction via gesture recognition. Current approaches involve utilization of a radar system that transmits a fixed signal with predetermined frequency, bandwidth, and other waveform parameters. However, gesture recognition accuracy can be greatly impacted by radar transmission parameters, which affect computational load and performance. In this work, we introduce a human-centered, fully adaptive radar (HC-FAR) system for ambient gesture recognition in which a programmable, software-defined radar system dynamically changes its RF transmission in response to human behavior. We design and switch between different transmission modes for different human-computer interaction tasks-human presence detection, trigger detection, and command translation-as well as alter processing so as to minimize computational load. In this way, the proposed HC-FAR paradigm enables dynamic management of the tradeoffs between dimensionality of RF data representations and their resulting computational load with real-time classification accuracy. Our results show that HC-FAR significantly reduces the allocation of computational and spectral resources, while enhancing fine-grain gesture recognition via a joint domain multi-input deep neural network, which takes as input the RF micro-Doppler signature, range, and angle profile.

Mosaic loss of the Y chromosome (mLOY) is the most common somatic event in men, strongly associated with aging and various health conditions. Current methods for detecting mLOY primarily rely on DNA genotyping arrays. Here, we present MosCoverY, a method for estimating mLOY from exome or whole-genome sequencing data. MosCoverY addresses the challenges posed by the structure of the Y chromosome by focusing on single-copy genes and normalizing their coverage against autosomal exons matched by length and GC content. We validated it using data from 212,062 male participants in the UK Biobank, comparing the results to those obtained using genotyping-or whole-genome-sequencing-based methods. MosCoverY identified mLOY in 5.6% of men, demonstrating performance that was comparable to the other methods. We validated our approach by replicating known mLOY associations with age, smoking, all-cause mortality, and germline genetic loci. We further confirmed the robustness of our method at lower sequencing depth and demonstrated its applicability in single-sample analysis. Finally, we used data from The Cancer Genome Atlas to demonstrate that MosCoverY can also reliably detect variable mLOY in tumoral genomes. MosCoverY offers a valuable tool for detecting mLOY from exome or genome data in population-scale studies.

T helper cell subsets-Th1, Th2, and Th17-coordinate pathogen-specific immune responses. Candida albicans-specific T cells include protective Th17 cells alongside other Th subsets. However, the role of alternative Th subsets remains unclear, particularly in individuals with impaired Th17 responses and recurrent candidiasis. Here, we show that patients with STAT1 gain-of-function mutations and chronic mucocutaneous candidiasis have a numerically normal but functionally altered pool of C. albicans-specific Th cells, skewed toward Th1 and Th2. This imbalance persisted even when assessing responses to the known and the newly identified immunodominant C. albicans antigens MP65 (65-kilodalton mannoprotein), HYR1 (hyphally regulated cell wall protein 1), and SAP4-6 (secreted aspartic proteinases 4-6), suggesting that antigen recognition and priming remain intact despite qualitative defects in T cell polarization. Using mucosal infection mouse models, we demonstrate that C. albicans-specific transgenic Th17 cells are sufficient to control infection, whereas Th1 and Th2 cells fail to protect, even in high numbers. Moreover, co-transfer of Th2 cells with Th17 cells impaired fungal control via an IL-4-dependent mechanism. These findings highlight the essential role of Th17 cells in protective immunity against C. albicans and reveal that non-Th17 responses are ineffective and may contribute to susceptibility in both humans and mice.

Background: Vitiligo is a chronic autoimmune skin depigmenting disorder, with a major impact on quality of life. Therapeutic options are still limited, with only one topical JAK inhibitor being approved by the US Food and Drug Administration. Although vitiligo is primarily regarded as a TH1/interferon-driven disease, emerging evidence suggests the involvement of additional immune axes, but their relevance to disease pathogenesis remains unclear. Objective: We sought to obtain a global cutaneous transcriptomic profile of lesional and nonlesional vitiligo. Methods: We performed bulk RNA sequencing combined with real-time PCR and immunohistochemistry of skin biopsy samples from 15 lesional and nonlesional vitiligo samples and compared them to 14 matched healthy controls. Results were corroborated by single-cell RNA sequencing. Results: Robust inflammatory dysregulation was captured not only in lesional but also nonlesional vitiligo skin relative to healthy controls. Lesional samples demonstrated upregulation of TH1 (OASL, CXCL9, CXCL10), TH2 (IL4, IL4R, CCL13, CCL17, CCL22, CCL26), and TH17/22 (IL20, S100A7, S100A8, S100A9, PI3) related markers. Similarly, nonlesional samples demonstrated activation of TH1 (CXCL9, OASL), TH2 (IL4R, IL10, CCL13, CCL17, CCL22), and TH17/22 (PI3, DEFB4A) associated markers. Clinical severity scores (Vitiligo Area Scoring Index and/or Vitiligo Disease Activity Index) significantly and positively correlated with multiple inflammatory mediators (ie, CXCL14, IL25, IL17RC) in lesional and/or nonlesional vitiligo skin. On a single-cell level, IL13 and IFNG expression were primarily found in nonlesional helper T cells and in lesional proliferating T cells, respectively. Conclusions: Our findings show that immune dysregulation in vitiligo involves immune axes beyond TH1/Tc1, with particular upregulation of type 2 markers already observed in nonlesional skin, suggesting a role during early lesion formation. (J Allergy Clin Immunol 2025;156:993-1007.)

BackgroundRed mullet (Mullus barbatus) is a key species in Mediterranean fisheries, yet its stock structure and population dynamics remain poorly understood due to a lack of comprehensive genomic resources. This study provides the first high-quality reference genome for M. barbatus and a comprehensive set of SNP markers to investigate its population structure and adaptive potential across the Mediterranean.ResultsUsing the newly generated chromosome-level reference genome, we re-analyzed a Mediterranean-wide reduced-representation genomic dataset. Our analysis reveals a panmictic population structure with strong genetic connectivity across the species' range, likely driven by extensive larval dispersal and multigenerational gene flow. Despite minimal genome-wide differentiation, outlier analysis identified candidate loci under directional selection, linked to key biological processes such as ontogeny and environmental adaptation.ConclusionsThis study presents the first genomic resource for M. barbatus, providing valuable insights into its genetic structure and adaptive mechanisms. While the identification of loci under selection offers promising leads, these findings are preliminary due to the limited genomic coverage of the dataset. Nonetheless, they pave the way for future genomic studies to explore how M. barbatus adapts to environmental and anthropogenic pressures. These results hold significant implications for the sustainable management of Mediterranean fisheries, especially in the context of climate change and conservation.

Juvenile hormones (JH) regulate insect development, reproduction, and behavior. The JH analog Methoprene, widely used in pest control, disrupts these processes by inhibiting maturation rather than causing mortality. Beyond its physiological effects, Methoprene influences insect behavior, including mate choice, social organization, and foraging, by altering neuronal sensitivity and gene expression via the Methoprene-tolerant receptor. These behavioral disruptions may negatively impact insect populations, including pollinators like honeybees. While laboratory studies highlight Methoprene's behavioral consequences, field research is needed to assess its ecological effects. Understanding these broader impacts is crucial for evaluating the risks associated with JH-based pest control strategies.